Paraquat Group Research Articles

The effects of Crocus sativus extract on inhaled paraquat-induced lung inflammation, oxidative stress, pathological changes and tracheal responsiveness in rats

Paraquat is a green liquid toxin that is used in agriculture and can induce multi-organ including lung injury. Various pharmacological effects of Crocus sativus (C. sativus) were indicated in previous studies. In this research, the effects of C. sativus extract and pioglitazone on inhaled paraquat-induced lung inflammation, oxidative stress, pathological changes, and tracheal responsiveness were studied in rats. Eight groups of rats (n = 7 in each) including control (Ctrl), untreated paraquat aerosol exposed group (54 mg/m3, 8 times in alternate days), paraquat treated groups with dexamethasone (0.03 mg/kg/day, Dexa) as positive control, two doses of C. sativus extract (20 and 80 mg/kg/day, CS-20 and CS-80), pioglitazone (5 and 10 mg/kg/day, Pio-5 and Pio-10), and the combination of CS-20 + Pio-5 were studied. Total and differential WBC, levels of oxidant and antioxidant biomarkers in the BALF, lung tissue cytokine levels, tracheal responsiveness (TR), and pathological changes were measured. The levels of IFN-γ, IL-10, SOD, CAT, thiol, and EC50 were reduced, but MDA level, total and differential WBC count in the BALF and lung pathological changes were increased in the paraquat group (all, p < 0.001). The levels of IFN-γ, IL-10, SOD, CAT, thiol and EC50 were increased but BALF MDA level, lung pathological changes, total and differential WBC counts were reduced in all treated groups. The effects of C. sativus high dose and combination groups on measured parameters were equal or even higher than dexamethasone (p < 0.05 to p < 0.001). The effects of the combination of CS-20 + Pio-5 on most variables were significantly higher than CS-20 and Pio-5 alone (p < 0.05 to p < 0.001). C. sativus treatment improved inhaled paraquat-induced lung injury similar to dexamethasone and showed a synergistic effect with pioglitazone, suggesting possible PPAR-γ receptor-mediated effects of the plant.

Ferulic acid grafted into β-cyclodextrin nanosponges ameliorates Paraquat-induced human MRC-5 fibroblast injury.

Paraquat (PQ) is a commercially important and effective herbicide in the world. Nevertheless, it has higher toxicity causing acute organ damage and different complications, mainly in the lungs and kidneys. Ferulic acid (FA), 4-hydroxy-3-methoxycinnamic acid imposes multiple pharmacological impacts. No protective effect of FA on PQ poisoning-caused human embryonic lung fibroblast damage has not been reported. Despite their many beneficial effects, FA is characterized by poor water solubility, low bioavailability, and phytochemical instability. To solve the problem, β-cyclodextrin nanosponge (β-CD NSs) was utilized to increase the solubility of FA so that it was grafted into β-CD NSs to establish β-CD@FA NSs. The purpose of this work was to examine for the first time the protective effect of β-CD@FA NS on MRC-5 human lung cells damages induced by PQ poisoning. MTS assay was performed to investigate the viability of MRC-5 cells at different concentrations of FA/β-CD@FA NSs when cells were co-cultured with 0.2 μg/mL PQ. The flow cytometry study was carried out to determine apoptosis. Malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were detected using appropriate biochemistry kits. Compared with the PQ group, the cell activity, CAT, and SOD levels were significantly increased in the FA and chiefly in β-CD@FA NSs intervention groups, whereas apoptosis and MDA levels were markedly decreased. The inflammatory factors tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 22 (IL-22) were detected. The results demonstrate that β-CD@FA NSs can inhibit PQ-induced cell damage by enhancing antioxidant stress capacity and regulation of inflammatory responses.

Assessment of pulmonary fibrosis induced by paraquat using Al18F-NODA-FAPI-04 PET/CT.

The lack of a highly sensitive method to evaluate paraquat (PQ)-induced pulmonary fibrosis and predict disease progression remains an unresolved clinic issue. Fibroblast activation protein (FAP) may play an important role in the pathogenesis of PQ-induced pulmonary fibrosis. We aimed to evaluate the role of FAP in the PQ-induced pulmonary fibrosis and the utility of fibroblast activation protein inhibitor (FAPI) for positron emission tomography (PET) imaging in PQ-induced pulmonary fibrosis. In our study, two cases of PQ poisoning were presented and FAPI PET/CT was performed as a novel imaging technique. The uptake of FAPI increased in both cases of PQ poisoning. Animal experiments were then performed to validate the findings in the patients. Physiological FAPI lung uptake was higher in mice of the PQ group than in the control group. The results of histological analysis and Western blot were consistent with the findings of PET/CT imaging. The pulmonary fibrosis animal model was developed by intragastric gavage of PQ. PET/CT imaging was performed after injection of FAPI. Lung tissues of mice were collected for fibrosis assessment after imaging. Immunohistochemistry for FAP, histology and Western blot for collagen were performed to further validate the imaging findings. In conclusion, FAPI was involved in the pathogenesis of fibrosis induced by PQ, and PET/CT with FAPI could detect lung fibrogenesis, making it a promising tool to assess early disease activity and predict disease progression.

Evaluation of nano-curcumin against inhaled paraquat-induced lung injury in rats.

Acute lung injury (ALI) remains a significant source of morbidity and mortality in critically ill patients and currently there is no efficient therapy for this condition. The aim of this research was to evaluate the protective activity of nano-curcumin (nano-CU) as a natural anti-inflammatory and antioxidant agent, against inhaled paraquat (PQ)-induced lung injury. One group of rats was exposed to saline (control group, Ctrl) and six groups to PQ aerosol (54mg/m3 on alternate days 8 times, each time for 30min) treated with drinking water alone (group PQ), 2 and 8mg/kg nano-CU (nano + CU(L) and nano + CU(H)), 5mg/kg pioglitazone (PIO), nano-CU(L) + PIO or 0.03mg/kg dexamethasone (Dexa) for 16days after PQ exposure period. PIO and Dexa were intraperitoneal (ip) injected and nano-CU was administered orally (po), (6 rats in each group). In the PQ group, total and differential WBC counts, malondialdehyde (MDA) in the bronchoalveolar lavage fluid (BALF), interferon gamma (INF-γ) and interleukin 10 (IL-10) levels in the lung tissues, lung pathological changes, and tracheal responsiveness were increased but the BALF thiol, catalase (CAT) and superoxide dismutase (SOD) levels were reduced. In treated groups with nano-CU(H) and PIO + nano-CU(L), all measured variables, in Dexa and nano-CU(L) treated groups, most variables and in the PIO group only a few variables were improved. The improvement of most variables in the PIO + nano-CU(L) group was significantly higher than in the PIO and nano-CU(L) groups alone. Nano-CU ameliorated lung damage induced by inhaled PQ similar to dexa and a synergic effect between nano-CU and PIO was observed, suggesting, a possible PPAR-γ receptor-mediated effect of curcumin.

Melatonin ameliorates acute lung injury caused by paraquat poisoning by promoting PINK1 and BNIP3 expression

Paraquat (PQ) poisoning can result in multiple organ dysfunction syndrome, mainly manifesting as acute lung injury and acute respiratory distress syndrome. No specific cure exists for PQ poisoning. However, by scavenging mitochondrial DNA (mtDNA), the damage-associated molecular pattern during PQ poisoning, mitophagy can ameliorate the downstream inflammatory pathways activated by mtDNA. Melatonin (MEL), however, can promote the expression of PINK1 and BNIP3, which are key proteins involved in mitophagy. In this study, we first explored whether MT could reduce PQ-induced acute lung injury by affecting mitophagy in animal models, and then, we studied the specific mechanism associated with this process through in vitro experiments. We also evaluated MEL intervention in the PQ group, while inhibiting the expression of PINK1 and BNIP3, to further determine whether the protective effects of MEL are associated with its effect on mitophagy. We found that when the expression of PINK1 and BNIP3 was inhibited, MEL intervention could not reduce mtDNA leakage and the release of inflammatory factors caused by PQ exposure, suggesting that the protective effect of MEL was blocked. These results suggest that by promoting the expression of PINK1 and BNIP3 and activating mitophagy, MEL can reduce mtDNA/TLR9-mediated acute lung injury during PQ poisoning. The results of this study could provide guidance for the clinical treatment of PQ poisoning to reduce associated mortality.

Paraquat-induced systemic inflammation and oxidative stress in rats improved by Curcuma longa ethanolic extract, curcumin and a PPAR agonist

The effect of Curcuma longa (Cl) ethanolic extract, nano-curcumin (Cu) and a PPARγ activator, pioglitazone on inhaled paraquat (PQ)-induced systemic inflammation and oxidative stress was examined in the present study. Control rats were exposed to normal saline and PQ groups to 27 and 54 mg/m3 (PQ-L and PQ-H) aerosols. Nine other PQ-H groups were treated with Curcuma longa (Cl, 150 and 600 mg/kg/day), nano-curcumin (Cu, 2 and 8 mg/kg/day), pioglitazone (Pio, 5 and 10 mg/kg), low dose of Pio + Cl and Cu and dexamethasone (0.03 mg/kg/day) for 16 days after PQ exposure period (n = 8). Total and differential WBC counts, malondialdehyde (MDA) and TNF-α levels were increased but thiol, catalase (CAT), superoxide dismutase (SOD), IL-10 and IFN-γ levels were decreased in the blood in the both PQ groups (p < 0.05 to p < 0.001). Treatment with Dexa and both doses of Cl, Cu, and Pio improved all measured variables compared to the PQ-H group (p < 0.05 to p < 0.001). The improvements of most variables in the treated group with low dose of Pio + Cl and Cu were higher than the effects of three agents alone. Systemic inflammation and oxidative stress induced by inhaled PQ were improved by Cl, Cu and Pio. In addition, a synergic effect between Pio with those of Cl and Cu was shown, suggesting PPARγ mediated effects of the plant and its derivative Cu.

Therapeutic potential of amitriptyline for paraquat-induced pulmonary fibrosis: Involvement of caveolin-1-mediated anti-epithelial-mesenchymal transition and inhibition of apoptosis

ObjectiveTreatment of pulmonary fibrosis caused by paraquat (PQ) poisoning remains problematic. Amitriptyline (AMT) has multiple pharmacological effects. Here we investigated the anti-fibrotic effect of AMT on PQ-induced pulmonary fibrosis and its possible mechanism. MethodsC57BL/6 mice were randomly divided into control, PQ, PQ + AMT and AMT groups. Histopathology of the lungs, blood gas analysis, and levels of hydroxyproline (HYP), transforming growth factor β1 (TGF-β1) and interleukin 17 (IL-17) were measured. The siRNA transfection inhibited caveolin-1 in A549 cells, which induced epithelial-mesenchymal transition (EMT) by PQ and followed intervention with AMT. E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA) and caveolin-1 were studied by immunohistochemistry and western blot analysis. The apoptosis rate was measured by flow cytometry. ResultsCompared with the PQ group, the PQ + AMT group displayed mild pathological changes in pulmonary fibrosis, lower HYP, IL-17 and TGF- β1 levels in lung, but high TGF- β1 in serum. Levels of N-cadherin and α-SMA in the lungs were significantly decreased, but caveolin-1 was increased, while SaO2 and PaO2 levels were higher. Compared with the PQ group, the apoptosis rate, N-cadherin and α-SMA levels in A549 cells were significantly decreased after PQ treatment and high dose AMT intervention (p < 0.01). The expressions of E-cadherin, N-cadherin and α-SMA in the PQ-induced cells transfected with caveolin-1 siRNA or siControl RNA were significantly different (p < 0.01), but the apoptosis rate was unaltered. ConclusionAMT inhibited PQ-induced EMT in A549 cells and improved lung histopathology and oxygenation in mice by up-regulating caveolin-1.

Effect of pirfenidone on paraquat-induced pulmonary fibrosis in rats

Objective: To construct paraquat (PQ) poisoning rat model and to explore the effect of pirfenidone (PFD) on PQ-induced pulmonary fibrosis. Methods: In April 2017, male 6-8 week-old Wistar rats were selected, and PQ was administered intraperitoneally at one time. PFD was administered by gavage 2 hours after poisoning. The daily gavage doses were 100, 200 and 300 mg/kg, and the rats were divided into physiological saline group, PQ group, PQ+PFD 100 group, PQ+PFD 200 group, PQ+PFD 300 group, with 10 rats in each group at each observation time point. The pathological changes of lung tissue at different time points (the 1st, 3rd, 7th, 14th, 28th, 42nd and 56th days) after poisoning and the effect of PFD intervention with different dose on PQ-induced pulmonary fibrosis were observed. Pathological evaluation of lung tissue was performed by Ashcroft scale method. The PQ+PFD 200 group was selected to further explore the pathological changes of lung tissue, the contents of hydroxyproline and malondialdehyde in lung tissue were determined.And the tumor necrosis factor (TNF) -α, interleukin (IL) -6, transforming growth factor (TGF) -β1, fibroblast growth factor (FGF) -B, platelet-derived growth factor (PDGF) -AB, insulin-like growth factor (IGF) -1 and PQ concentrations in serum and lung tissue were determined. Results: On the 1st to 7th day after PQ exposure, rats developed lung inflammation, which was aggravated on the 7th to 14th day, and pulmonary fibrosis appeared on the 14th to 56th day. Compared with PQ group, the Ashcroft scores of lung fibrosis in PQ+PFD 200 group and PQ+PDF 300 group decreased significantly in 7th and 28th day (P<0.05), while the Ashcroft score of lung fibrosis in PQ+PFD 100 group had no significant difference (P>0.05). After PQ exposure, the content of hydroxyproline in lung tissue increased gradually and reached the peak value on the 28th day. Compared with the PQ group, the contents of hydroxyproline in the PQ+PFD 200 group decreased at the 7th, 14th and 28th day, and the contents of malondialdehyde decreased at the 3rd and 7th day, the differences were statistically significant (P<0.05). The levels of TNF-α, IL-6 in rat serum and lung tissue reached the peak value on the 7th day after PQ exposure, and the levels of TGF-β1, FGF-B and IGF-1 in rat serum and lung tissue reached the peak value on the 14th day after PQ exposure, and the level of PDGF-AB in rat serum and lung tissue reached the peak value on the 28th day after PQ exposure. Compared with PQ group, the level of serum IL-6 in PQ+PFD 200 group decreased significantly on the 7th day, and serum TGF-β1, FGF-B, PDGF-AB and IGF-1 on the 14th and 28th day were decreased significantly (P<0.05). The levels of TNF-α, IL-6 in lung tissue of rats in PQ+PFD 200 group on the 7th day decreased significantly, and the levels of TGF-β1, FGF-B and IGF-1 in lung tissue of rats on the 14th day were significantly decreased, and the level of PDGF-AB in lung tissue of rats on the 28th day were significantly decreased (P<0.05) . Conclusion: PFD partially alleviates the PQ-induced lung inflammation and fibrosis by inhibiting oxidative stress, reducing the levels of pro-inflammatory and pro-fibrotic cytokines in serum and lung tissue, but does not affect the concentrations of PQ in serum and lung tissue.

Andrographolide alleviates paraquat-induced acute lung injury by activating the Nrf2/HO-1 pathway.

Paraquat (PQ), a highly effective and rapidly non-selective herbicide, mainly targets the lungs and causes acute lung injury (ALI). So far, the scarcity of effective drug candidates against PQ-induced ALI remains a big challenge. Andrographolide (Andro), with its anti-inflammatory and antioxidant activities, has been demonstrated to alleviate ALI. Nevertheless, whether Andro could alleviate the PQ-mediated ALI remains unknown. Therefore, this study will explore the effects as well as the possible mechanism of Andro against ALI caused by PQ. C57BL/6J mice were injected with 20 mg/kg PQ intraperitoneally to establish an ALI model. PQ-treated MLE-12 cells were applied to a vitro model. Nuclear factor erythroid like-2 (Nrf2) was knocked out to explore the specific effects of the Nrf2/ Heme oxygenase-1 (OH-1) pathway in the protection of Andro against ALI caused by PQ. Andro significantly reduced lung damage and the ratio of Wet/Dry (W/D) weight, decreased MDA, IL-6, IL-1β, and TNF-ɑ levels, reversed the decrease of CAT and SOD levels, and inhibited apoptosis caused by PQ. Andro obviously increased the ratio of Bcl-2/Bax while reducing caspase-3 and cleaved caspase-3 levels. Furthermore, Andro dramatically elevated the antioxidant proteins Nrf2, NQO-1, and HO-1 levels compared with the PQ group. This experiment demonstrated that Andro reduced ROS and inhibited apoptosis, induced by PQ in MLE-12 cells, by inducing Nrf2/HO-1 pathway activation. Andro effectively ameliorates oxidant stress and apoptosis in ALI caused by PQ, possibly through inducing Nrf2/HO-1 pathway activation.

Investigating Preventive Effect of Vitamin D and N-acetylcysteine Against Kidney Injury in Rats Versus the Promotive Effect of Paraquat

Background: Paraquat (PQ) is one of the most important herbicides used in agriculture. Objectives: This study was conducted to compare the preventive effect of vitamin D (Vit D) and N-acetylcysteine (NAC) against kidney injury in rats versus the promotive effect of PQ. Methods: In this study, rats were divided into six groups. The control group (group 1) received normal saline, Vit D group (group 2) received intraperitoneal (IP) injections of+Vit D (2 μg/kg), NAC group (group 3) received NAC (6.25 mg/kg, IP), PQ group (group 4) received PQ (5 mg/kg/d, IP), PQ+Vit D group (group 5) received PQ+Vit D (5 mg/kg/d+2 μg/kg/d, IP) and PQ+NAC group (group 6) received PQ+NAC (5 mg/kg/d+6.25 mg/kg/d, IP). The animals were treated for 7 consecutive days as a sub-chronic exposure. After the collection of urea and serum creatinine, biomarkers of oxidative stress and kidney histopathology were investigated. Results: PQ increased lipid peroxidation (LPO), urea, and serum creatinine, but it significantly decreased total antioxidant capacity (TAC) and thiol groups. In the groups treated with Vit D and NAC, it was observed that LPO, urea, and creatinine significantly decrease compared with the PQ group, and TAC, thiol groups, and Vit D levels increased in kidney tissue. Conclusion: The obtained findings revealed that both Vit D and NAC used as preventive compound were able to reduce oxidative stress and tissue damage caused by PQ toxicity in the kidney.

Nanocrocin Protective Effects on Paraquat-Induced Oxidative Stress in the MRC-5 Cell Line.

Paraquat (PQ) herbicide poisoning is a severe medical problem in developing countries without suitable therapy. This study aimed to investigate the effects of crocin (CCN) and nano crocin (NCCN) on PQ -induced toxicity in the MRC-5 cell line. The results showed that the particle size of NCCN was 140.3 ± 18.0nm, and the zeta potential of the optimal crocin-loaded niosomes was 23.4 ± 2.8mV. The NCCN was more effective than CCN in the inhibition of PQ-induced toxicity. Treatment of the MRC-5 cells leads to a decrease in ROS and an increase in SOD, CAT, GPX, and TAC levels in PQ-CCN and PQ-NCCN groups compared with the PQ group. These changes tended to be positively associated with the NCCN compared to CCN. Overall, NCCN was more effective than crocin in treating PQ-induced toxicity in vitro and deserved further preclinical consideration.

Effect of taurine on histopathological features of spermatogenesis in seminiferous tubules of mice (Mus musculus) induced by paraquat

This study aimed to determine the effect of taurine on the enhancement of the spermatogenetic process in male mice (Mus musculus) induced by paraquat (PQ). Twenty-five male mice (Mus musculus) aged 2-3 months with a bodyweight of around 35 grams were divided randomly into five groups. The K + and the treatment group (P1, P2, and P3) mice were induced using PQ. PQ was given intraperitoneally (IP) twice a week for 21 consecutive days at a dose of 30 mg/kg BW. Two hours after the administration of PQ, P1, P2, and P3 groups were given taurine at a dose of 250, 500, and 1000 mg/kg BW/day for three weeks (Heidari et al., 2019). K- group was given distilled water (IP) only. On day-29, mice were sacrificed for testicles histopathological preparations with hematoxylin-eosin staining. Results showed that the mice exposed to PQ only (the K+ group) had a reduced spermatogenesis score compared to those of the K- group (p &lt;0.05). Taurine treatment on PQ-exposed mice was followed by an increase spermatogenesis score. The optimal curative dose of taurine was 500 mg/kg (P2 group). However, a higher dose (1000 mg/kg BW) of taurine resulted in a decline in the spermatogenesis score than those of at the 500 mg/kg. It could be concluded that treatment with taurine could enhance the spermatogenetic process of male mice (Mus musculus) induced by PQ.

Anthrahydroquinone-2,6-disulfonate alleviates paraquat-induced kidney injury via the apelin-APJ pathway in rats

Objective: To explore the protective effects of anthrahydroquinone- 2,6-disulfonate (AH2QDS) on the kidneys of paraquat (PQ) poisoned rats via the apelin-APJ pathway. Methods: Male Sprague Dawley rats were divided into four experimental groups: control, PQ, PQ+sivelestat, and PQ+AH2QDS. The PQ+sivelestat group served as the positive control group. The model of poisoning was established via intragastric treatment with a 20% PQ pesticide solution at 200 mg/kg. Two hours after poisoning, the PQ+sivelestat group was treated with sivelestat, while the PQ+AH2QDS group was given AH2QDS. Six rats were selected from each group on the first, third, and seventh days after poisoning and dissected after anesthesia. The PQ content of the kidneys was measured using the sodium disulfite method. Hematoxylin-eosin staining of renal tissues was performed to detect pathological changes. Apelin expression in the renal tissues was detected using immunofluorescence. Western blotting was used to detect the expression levels of the following proteins in the kidney tissues: IL- 6, TNF-α, apelin-APJ (the apelin-angiotensin receptor), NF-κB p65, caspase-1, caspase-8, glucose-regulated protein 78 (GRP78), and the C/EBP homologous protein (CHOP). In in vitro study, a PQ toxicity model was established using human tubular epithelial cells treated with standard PQ. Twenty-four hours after poisoning, sivelestat and AH2QDS were administered. The levels of oxidative stress in human renal tubular epithelial cells were assessed using a reactive oxygen species fluorescence probe. Results: The PQ content in the kidney tissues of the PQ group was higher than that of the PQ+AH2QDS group. Hematoxylin-eosin staining showed extensive hemorrhage and congestion in the renal parenchyma of the PQ group. Vacuolar degeneration of the renal tubule epithelial cells, deposition of crescent-like red staining material in renal follicles, infiltration by a few inflammatory cells, and a small number of cast formation were also observed. However, these pathological changes were less severe in the PQ+sivelestat group and the PQ+AH2QDS group (P&lt;0.05). On the third day after poisoning, immunofluorescence assay showed that the level of apelin in the renal tissues was significantly higher in the PQ+AH2QDS group than in the PQ group. Western blotting analysis results showed that IL-6, TNF-α, NF-κB p65, caspase-1, caspase-8, GRP78, and CHOP protein levels in the PQ group were higher than in the PQ+AH2QDS group (P&lt;0.05). The expression of apelin-APJ proteins in the PQ+AH2QDS group was higher than in the PQ+sivelestat and PQ groups (P&lt;0.05); this difference was significant on Day 3 and Day 7. The level of oxidative stress in the renal tubular epithelial cells of the PQ+AH2QDS group and the PQ+sivelestat group was significantly lower than in the PQ group (P&lt;0.05). Conclusions: This study confirms that AH2QDS has a protective effect on PQ-poisoned kidneys and its positive effect is superior to that of sivelestat. The mechanism of the protective effects of AH2QDS may be linked to reduction in cellular oxidative stress, PQ content of renal tissue, inflammatory injury, endoplasmic reticulum stress, and apoptosis. AH2QDS may play a role in the treatment of PQ poisoning by upregulating the expression of the apelin-APJ.

A dose-related positive effect of inhaled simvastatin-loaded PLGA nanoparticles on paraquat-induced pulmonary fibrosis in rats.

Pulmonary fibrosis is an important complication of subacute paraquat (PQ) poisoning. Here, we reported a novel nanotherapeutic platform for PQ-induced pulmonary fibrosis in animal inhalation models using simvastatin (SV)-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Eight inhalations of normal saline, PQ (24 mg/kg), PQ plus SV (20 mg/kg), PQ plus SV-loaded PLGA NPs at doses of 5, 10 or 20 mg/kg or PQ plus PLGA NPs were given to rats. After the end of the treatment period, inflammatory factors and creatine phosphokinase as well as lung pathological changes and tracheal responsiveness were evaluated. Inhalation of SV-loaded PLGA NPs could significantly prevent the progression of PQ-induced pulmonary fibrosis especially at a dose of 10mg through decreasing the serum level of inflammatory factors as well as contractile responses (p < 0.001) compared to PQ group. Pathological findings also confirmed the results. However, inhalation of non-formulated SV could not prevent tissue damage and fibrosis in comparision with SV-loaded PLGA NPs. Taken together, the present work provides us an idea about the pulmonary delivery of PLGA-SV NPs using nebulizer for the treatment of PQ poisoning. However, the efficacy of this formulation in human beings and clinical use needs to be more investigated.

Identification of differentially expressed genes and pathways in diquat and paraquat poisoning using bioinformatics analysis

Objective: In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Methods: Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein–protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Results: Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions: These pathways and DEGs may serve as targets for gene therapy.

Protective Effects of N-acetylcysteine Niosome Nanoparticles on Paraquatinduced Nephrotoxicity in Male Rats.

Paraquat (PQ), as a bipyridyl compound, is widely used as an effective herbicide that produces reactive oxygen species (ROS), affecting the unsaturated lipids of cell membranes leading to cell mortality. N-acetylcysteine (NAC) is a medication that has a beneficial role in reducing the intoxication of kidneys caused by PQ. Niosomes are bilayer vesicles that enhance the bioavailability of drugs. This study aimed to compare the effects of NAC and niosome of NAC (NACNPs) on PQ-induced kidney toxicity concerning its antioxidant activity. In this experimental study, after formulating NACNP, 30 Wistar male rats weighing 180 to 250 gm were classified into five groups: the control group was treated with normal saline, while the other four groups received 35mg/kg/day of PQ via intraperitoneal route and, was treated with 25mg/kg/day NAC, 25mg/kg/day niosome and 25 mg/kg/day NACNP by gavage, Then, oxidative stress biomarkers such as total antioxidant capacity (TAC), catalase activity (CAT), lipid peroxidation (LPO), and total thiol group (TTG), plus blood urea nitrogen (BUN) and creatinine levels were evaluated in kidney tissue homogenate and examined histopathologically. The results revealed that TTG increased significantly in NAC & NACNP groups than in the PQ group. Further, in the PQ group, LPO increased significantly compared with the control, NAC, and NACNP groups, while in the NAC and NACNP group, LPO diminished compared with the PQ group. There was no significant difference in TAC between groups. Blood urea nitrogen (BUN) and creatinine levels dropped in NACNP compared with the PQ group and the NAC. Histological studies also approved PQ-induced damage and the protective effect of NACNP. The results indicated that NACNP could modulate oxidative stress status and kidney function against PQ toxicity.

JAK2/STAT3 pathway regulates microglia polarization involved in hippocampal inflammatory damage due to acute paraquat exposure

ObjectiveTo explore the effects of acute paraquat (PQ) exposure on the phenotypic polarization of hippocampal microglia and its mechanism. MethodsAn acute PQ exposure rat model was established. Male SD rats were exposed to 0, 5, 25, and 50 mg/kg PQ, and brain hippocampal tissue was collected after 1, 3, and 7 days of exposure, respectively. Hippocampal pathological changes were examined by H&E staining, and immunohistochemistry (IHC) was used to detect changes in the number of Iba-1-positive cells, the average number of endpoints, and the average process length. The protein expression of Iba-1 was detected by western blotting. BV-2 microglia were treated with 0, 0.01, 0.025, 0.05, or 0.1 μmol/L PQ for 24 h. ELISA and western blotting assays were performed to detect the expression of TNF-α and IL-1β in vivo and in vitro. The M1 microglia marker iNOS, the M2 microglia marker Arg-1, and the p-JAK2 and p-STAT3 protein were detected by western blotting. JAK2/STAT3 pathway activation role in regulating microglia phenotypic polarization was further validated in vivo and in vitro by JAK2-specific inhibitor AG490 administration. ResultsAfter acute PQ exposure, hippocampal neurons showed pathological changes such as loose arrangement and nuclear pyknosis, the number of Iba-1 positive cells and the expression of Iba-1 protein increased, and the average number of endpoints and average process length of microglia decreased. Histological examination revealed that compared with the control group, in the 50 mg/kg PQ group on the 3rd and 7th day, the expression of TNF-α, IL-1β, and iNOS significantly increased, while that of Arg-1 significantly decreased. p-JAK2 and p-STAT3 expression significantly increased in the 50 mg/kg PQ group on the 1st, 3rd, and 7th day. In vitro, compared with the control group, the expression of TNF-α, IL-1β, iNOS, p-JAK2, and p-STAT3 significantly increased, while Arg-1 expression was significantly reduced in the 0.025, 0.05, and 0.1 μmol/L PQ groups. After AG490 administration, the expression levels of p-JAK2, p-STAT3, iNOS, TNF-α, and IL-1β in the AG490 +PQ group were significantly inhibited in vivo and in vitro compared with the PQ-only group. On the contrary, Arg-1 expression was significantly increased. ConclusionOur results suggest that acute PQ exposure may induce M1-type polarization of hippocampal microglia by activating the JAK2/STAT3 pathway, which in turn releases pro-inflammatory factors such as TNF-α and IL-1β, leading to hippocampal inflammatory damage.

Comparative effects of Curcuma longa and curcumin on paraquat-induced systemic and lung oxidative stress and inflammation in rats.

Objective:Comparative effect of Curcuma longa (C. longa) ethanolic extract and curcumin on paraquat (PQ)-induced systemic and lung oxidative stress and inflammation were evaluated in the present study.Materials and Methods:Control animals were exposed to normal saline and PQ group to 54 mg/m3 PQ aerosols (8 times, each time for 30 min). Treatment groups were exposed to PQ and treated with 150 and 600 mg/kg/day C. longa, or 30 and 120 mg/kg/day curcumin after PQ exposure period for 16 days. Total and differential white blood cells (WBC) and oxidative markers were measured both in bronchoalveolar lavage (BALF) and blood at the end of the study.Results:Total and differential WBC counts as well as malondialdehyde (MDA) level were significantly increased but total thiol content and the activities of catalase (CAT) and superoxide dismutase (SOD) were reduced in both the BALF and blood of the PQ group in comparison with the control group (p<0.05 to p<0.001). Both doses of C. longa and curcumin diminished MDA level, total and differential WBC counts in the blood and BALF but increased CAT and SOD activities in both of them compared to PQ group (p<0.05 to p<0.001). The effects of C. longa and curcumin high dose on most variables were markedly more than low dose (p<0.05 to p<0.001). Furthermore, the effects of curcumin on some variables were markedly more than C. longa (p<0.05 to p<0.001).Conclusion:Both C. longa and curcumin improved PQ-induced systemic and lung inflammation and oxidative stress, but the effect of curcumin was more prominent.

5‑Aminosalicylic acid attenuates paraquat‑induced lung fibroblast activation and pulmonary fibrosis of rats.

Pulmonary fibrosis is one of the most important pathological processes associated with paraquat (PQ) poisoning. 5‑Aminosalicylic acid (5‑ASA) has been shown to be a promising agent against fibrotic diseases. In the present study, the alleviating role of 5‑ASA was evaluated in a rat model of pulmonary fibrosis induced by PQ intragastric poisoning (80mg/kg). Wistar rats were divided into control, PQ, 5‑ASA (30mg/kg daily, 14days) and PQ + 5‑ASA groups. Histological examination revealed congestion, edema and inflammatory cell infiltration in the bronchial and alveolar walls at3days after PQ exposure. Alveolar septum thickening with alveolar lumen narrowing was observed at14days, while fibroblast proliferation, increase in collagen fiber number and fibrous thickening of the alveolar walls were observed at28day. All the aforementioned pulmonary injury changes in the PQ group were attenuated in the PQ + 5‑ASA group. Hydroxyproline (HYP) content increased in the lung tissues of the rats at14days after PQ treatment and reached a peak at28days. Compared with the PQ group, HYP contents of lung tissue decreased at14and28days after PQ + 5‑ASA treatment. Masson's trichrome staining revealed that the increase in the amount of collagen fibers in the lung tissues of rats in the PQ group was inhibited by 5‑ASA treatment, further confirming the alleviating effect of 5‑ASA on fibrosis. In addition, the results showed that 5‑ASA attenuated the upregulation of transforming growth factor‑β1 and phosphorylated‑SMAD3, and the reduction of peroxisome proliferator activated receptor γ induced by PQ in lung tissue of rats and human lung fibroblast WI‑38 VA13 cells. In conclusion, the results suggested that 5‑ASA had an alleviating effect on PQ‑induced pulmonary fibrosis, partly by suppressing the activation of the TGF‑β1 signaling pathway.

Anthrahydroquinone-2-6-disulfonate is a novel, powerful antidote for paraquat poisoning

Paraquat (PQ) is a widely used fast-acting pyridine herbicide. Accidental ingestion or self-administration via various routes can cause severe organ damage. Currently, no effective antidote is available commercially, and the mortality rate of poisoned patients is exceptionally high. Here, the efficacy of anthrahydroquinone-2-6-disulfonate (AH2QDS) was observed in treating PQ poisoning by constructing in vivo and ex vivo models. We then explored the detoxification mechanism of AH2QDS. We demonstrated that, in a rat model, the PQ concentration in the PQ + AH2QDS group significantly decreased compared to the PQ only group. Additionally, AH2QDS protected the mitochondria of rats and A549 cells and decreased oxidative stress damage, thus improving animal survival and cell viability. Finally, the differentially expressed genes were analysed in the PQ + AH2QDS group and the PQ group by NextGen sequencing, and we verified that Nrf2’s expression in the PQ + AH2QDS group was significantly higher than that in the PQ group. Our work identified that AH2QDS can detoxify PQ by reducing PQ uptake and protecting mitochondria while enhancing the body's antioxidant activity.